title: The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death.
abstract: Pharmacological inhibition of autophagic-lysosomal function has recently emerged as a promising strategy for chemotherapeutic intervention targeting cancer cells. Repurposing approved and abandoned non-oncological drugs is an alternative approach to the identification and development of anticancer therapeutics, and antimalarials that target autophagic-lysosomal functions have recently attracted considerable attention as candidates for oncological repurposing. Since cumulative research suggests that dependence on autophagy represents a specific vulnerability of malignant melanoma cells, we screened a focused compound library of antimalarials for antimelanoma activity. Here we report for the first time that amodiaquine (AQ), a clinical 4-aminoquinoline antimalarial with unexplored cancer-directed chemotherapeutic potential, causes autophagic-lysosomal and proliferative blockade in melanoma cells that surpasses that of its parent compound chloroquine. Monitoring an established set of protein markers (LAMP1, LC3-II, SQSTM1) and cell ultrastructural changes detected by electron microscopy, we observed that AQ treatment caused autophagic-lysosomal blockade in malignant A375 melanoma cells, a finding substantiated by detection of rapid inactivation of lysosomal cathepsins (CTSB, CTSL, CTSD). AQ-treatment was associated with early induction of energy crisis (ATP depletion) and sensitized melanoma cells to either starvation- or chemotherapeutic agent-induced cell death. AQ displayed potent antiproliferative effects, and gene expression array analysis revealed changes at the mRNA (CDKN1A, E2F1) and protein level (TP53, CDKN1A, CCND1, phospho-RB1 [Ser 780]/[Ser 807/811], E2F1) consistent with the observed proliferative blockade in S-phase. Taken together, our data suggest that the clinical antimalarial AQ is a promising candidate for repurposing efforts that aim at targeting autophagic-lysosomal function and proliferative control in malignant melanoma cells.
authors.affiliation: Department of Pharmacology and Toxicology; College of Pharmacy and Arizona Cancer Center; University of Arizona; Tucson, AZ USA.
authors.forename: Shuxi
authors.initials: S
authors.lastname: Qiao
authors.forename: Shasha
authors.initials: S
authors.lastname: Tao
authors.forename: Montserrat
authors.initials: M
authors.lastname: Rojo de la Vega
authors.forename: Sophia L
authors.initials: SL
authors.lastname: Park
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Vonderfecht
authors.forename: Suesan L
authors.initials: SL
authors.lastname: Jacobs
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
authors.forename: Georg T
authors.initials: GT
authors.lastname: Wondrak
mesh_terms: D000655:Amodiaquine / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000962:Antimalarials; D000655:Amodiaquine
keywords: CDKN1A; E2F1; amodiaquine; autophagy; cathepsin; chloroquine; lysosome; malignant melanoma